Aldrin (CASRN 309-00-2)

Human health assessment information on a chemical substance is included in the IRIS database only after a comprehensive review of toxicity data, as outlined in the IRIS assessment development process. Sections I (Health Hazard Assessments for Noncarcinogenic Effects) and II (Carcinogenicity Assessment for Lifetime Exposure) present the conclusions that were reached during the assessment development process. Supporting information and explanations of the methods used to derive the values given in IRIS are provided in the guidance documents located on the IRIS website.

STATUS OF DATA FOR Aldrin

File First On-Line 03/31/1987

Category (section)

Status

Last Revised

Oral RfD Assessment (I.A.)

on-line

03/01/1988

Inhalation RfC Assessment (I.B.)

no data

Carcinogenicity Assessment (II.)

on-line

07/01/1993

_I.
Chronic Health Hazard Assessments for Noncarcinogenic Effects

_I.A.
Reference Dose for Chronic Oral Exposure (RfD)

Substance Name — Aldrin
CASRN — 309-00-2
Last Revised — 03/01/1988

The oral Reference Dose (RfD) is based on the assumption that thresholds
exist for certain toxic effects such as cellular necrosis. It is expressed
in units of mg/kg-day. In general, the RfD is an estimate (with uncertainty
spanning perhaps an order of magnitude) of a daily exposure to the human
population (including sensitive subgroups) that is likely to be without
an appreciable risk of deleterious effects during a lifetime. Please refer
to the Background Document for an elaboration of these concepts. RfDs
can also be derived for the noncarcinogenic health effects of substances
that are also carcinogens. Therefore, it is essential to refer to other
sources of information concerning the carcinogenicity of this substance.
If the U.S. EPA has evaluated this substance for potential human carcinogenicity,
a summary of that evaluation will be contained in Section II of this file.

__I.A.2. Principal and Supporting Studies (Oral RfD)

Groups of 24 rats (12/sex) were fed aldrin in the diet
at levels of 0, 0.5, 2, 10, 50, 100, or 150 ppm for 2 years. Liver lesions
characteristic of chlorinated insecticide poisoning were observed at dose
levels of 0.5 ppm and greater. These lesions were characterized by enlarged
centrilobular hepatic cells, with increased cytoplasmic oxyphilia, and
peripheral migration of basophilic granules. A statistically significant
increase in liver-to-body weight ratio was observed at all dose levels.
Kidney lesions occurred at the highest dose levels. Survival was markedly
decreased at dose levels of 50 ppm and greater.

Additional data are fairly supportive. Effect and no-effect
levels are similar (to those found for rats) for liver effects in dogs
after 15 months' exposure to aldrin in the diet. Liver effects were observed
at slightly higher doses in several other subchronic-to-chronic rat and
dog studies. Short-term exposure to higher doses resulted in mortality
for a number of species.

__I.A.3.
Uncertainty and Modifying Factors (Oral RfD)

UF — The composite UF of 1000 encompasses the uncertainty
of extrapolation from animals to humans, the uncertainty in the range
of human sensitivities, and an additional uncertainty because the RfD
is based on a LOAEL rather than a NOAEL.

MF — None

__I.A.4.
Additional Studies/Comments (Oral RfD)

None.

__I.A.5.
Confidence in the Oral RfD

Study — Medium
Database — Medium
RfD — Medium

The principal study, designed as a carcinogenesis bioassay,
is strong in histopathologic analysis but lacks other toxicologic parameters,
and is therefore rated medium. The database is fairly extensive, and
generally supportive, but is rated medium because of the lack of NOELs
for some studies. Also, no chronic data exist for the dog, which may be
a more sensitive species than the rat. Medium confidence in the RfD follows.

Screening-Level Literature Review Findings — A screening-level review conducted by an EPA contractor of the more recent toxicology literature pertinent to the RfD for Aldrin conducted in September 2002 did not identify any critical new studies. IRIS users who know of important new studies may provide that information to the IRIS Hotline at hotline.iris@epa.gov or (202)566-1676.

__I.A.7.
EPA Contacts (Oral RfD)

Please contact the IRIS Hotline for all questions
concerning this assessment or IRIS, in general, at (202)566-1676 (phone),
(202)566-1749 (FAX) or hotline.iris@epa.gov
(internet address).

_I.B.
Reference Concentration for Chronic Inhalation Exposure (RfC)

_II.
Carcinogenicity Assessment for Lifetime Exposure

Substance Name — Aldrin
CASRN — 309-00-2
Last Revised — 07/01/1993

Section II provides information on three aspects of the
carcinogenic assessment for the substance in question; the weight-of-evidence
judgment of the likelihood that the substance is a human carcinogen, and
quantitative estimates of risk from oral exposure and from inhalation
exposure. The quantitative risk estimates are presented in three ways.
The slope factor is the result of application of a low-dose extrapolation
procedure and is presented as the risk per (mg/kg)/day. The unit risk
is the quantitative estimate in terms of either risk per ug/L drinking
water or risk per ug/cu.m air breathed. The third form in which risk is
presented is a drinking water or air concentration providing cancer risks
of 1 in 10,000, 1 in 100,000 or 1 in 1,000,000. The rationale and methods
used to develop the carcinogenicity information in IRIS are described
in The Risk Assessment Guidelines of 1986 (EPA/600/8-87/045) and in the
IRIS Background Document. IRIS summaries developed since the publication
of EPA's more recent Proposed Guidelines for Carcinogen Risk Assessment
also utilize those Guidelines where indicated (Federal Register 61(79):17960-18011,
April 23, 1996). Users are referred to Section I of this IRIS file for
information on long-term toxic effects other than carcinogenicity.

_II.A.
Evidence for Human Carcinogenicity

__II.A.1.
Weight-of-Evidence Characterization

Classification — B2; probable human carcinogen

Basis — Orally administered aldrin produced significant
increases in tumor responses in three different strains of mice in both
males and females. Tumor induction has been observed for structurally
related chemicals, including dieldrin, a metabolite.

__II.A.2.
Human Carcinogenicity Data

Inadequate. Two studies of workers exposed to aldrin and
dieldrin (a metabolite of aldrin) did not find these workers to have an
excess risk of cancer. Both studies, however, were limited in their ability
to detect an excess of deaths from cancer. Van Raalte (1977) observed
two cases of cancer (gastric and lymphosarcoma) among 166 pesticide manufacturing
workers exposed 4 to 19 years and followed from 15 to 20 years. Exposure
was not quantified, and workers were also exposed to other organochlorine
pesticides (endrin and telodrin). A small number of workers was studied,
the mean age of the cohort (47.7 years) was low, the number of expected
deaths was not calculated, and the duration of exposure and of latency
was relatively short.

In a retrospective mortality study, Ditraglia et al. (1981)
reported no increased incidence of deaths from cancer among 1155 organochlorine
pesticide manufacturing workers (31 observed vs. 37.8 expected, SMR=82).
This result was not statistically significant. Workers were employed for
6 or more months and followed for 13 or more years (24,939 person-years).
Workers with no exposure (for example, office workers) were included in
the cohort. Vital status was not known for 112 (10%) of the workers, and
these workers were assumed to be alive; therefore, additional deaths may
have occurred but were not observed. Exposure was not quantified and workers
were also exposed to other chemicals and pesticides (including endrin).
An increased incidence of deaths from cancer was seen at several specific
sites: esophagus (2 deaths observed, SMR=235), rectum (3, SMR=242); liver
(2, SMR=225), and lymphatic and hematopoietic system (6, SMR=147); but
these site-specific incidences were not statistically significant.

__II.A.3.
Animal Carcinogenicity Data

Sufficient. Davis and Fitzhugh (1962) fed a group of 215
male and female C3HeB/Fe mice a dietary mixture containing 10 ppm aldrin
for up to 2 years. The control group consisted of 217 mice. The aldrin-treated
mice died 2 months earlier than controls. Intercurrent disease, pneumonia,
and intestinal parasitism may have influenced the long-term survival rate.
A statistically significant increase of hepatomas was reported in the
treated animals as compared with controls. An independent reevaluation
of the liver lesions showed most of the hepatomas to be liver carcinomas
(Epstein, 1975). In a follow-up study, Davis (1965) administered aldrin
at 0 or 10 ppm in the diet to 100 male and 100 female C3H mice for 2 years.
The incidence of hepatic hyperplasia and benign hepatomas in the aldrin
group was approximately double that of controls, whereas the number of
hepatic carcinomas was about the same. Neither study provided a detailed
pathologic examination or data separated by sex.

Aldrin (95% pure) was administered in the diet to 50 male
and 50 female B6C3FI mice at TWA doses of 4 and 8 ppm or 3 and 6 ppm.
Treatment was for 80 weeks, and animals were observed for an additional
10 to 13 weeks (NCI, 1978). In male mice, there was a significant dose-related
increase in hepatocellular carcinomas when compared with matched or pooled
controls.

Treon and Cleveland (1955) administered aldrin in the
diet to 40 Carworth rats/sex at concentrations of 2.5, 12.5, or 25 ppm
for a period of 2 years. Forty animals/sex served as controls. Mortality
of the treated rats was greater than controls, with 50% surviving in the
2.5 and 12.5 ppm groups and 40% surviving in the 25 ppm group at the end
of the experiment. Cleveland (1966) reported that no apparent treatment-related
tumors were present in the above study. Deichmann et al. (1970) fed 50
male and 50 female Osborne-Mendel rats aldrin (95% pure) at final concentrations
of 20, 30, or 50 ppm for 31 months. Controls consisted of 100 rats/sex.
There was no evidence of carcinogenic response in male or female rats
fed aldrin. The NCI (1978) fed 50 Osborne-Mendel rats/sex aldrin (95%
pure) at 30 or 60 ppm. Male rats were treated 111 to 113 weeks and followed
for 37 to 38 weeks of observation, and female rats were treated for 80
weeks and followed for 32 to 33 weeks of observation. Aldrin produced
no significant effect on the mortality of the rats of either sex. The
tumors observed awere randomly distributed, with no apparent relationship
to aldrin treatment. Four additional bioassays observed no carcinogenic
effect of aldrin in rats, but were considered inadequate for carcinogenicity
assessment.

__II.B.3.
Additional Comments (Carcinogenicity, Oral Exposure)

Body weights for mice were assumed to be 0.03 kg for purposes
of dose conversion. The above data sets were used for calculation of the
following slope factors: 2.3E+1 per (mg/kg)/day for female C3H mice, 1.8E+1
per (mg/kg)/day for male C3H mice, and 1.2E+1 per (mg/kg)/day for male
B6C3F1 mice. No strain or sex specificity was noted in the studies, since
aldrin treatment induced liver tumors in all mouse strains tested. A geometric
mean of 1.7E+1 per (mg/kg)/day was thus chosen for the quantitative estimate,
since all three slope factors were very similar.

The unit risk should not be used if the water concentration
exceeds 20 ug/L, since above this concentration the unit risk may not
be appropriate.

__II.B.4.
Discussion of Confidence (Carcinogenicity, Oral Exposure)

Adequate numbers of animals were treated for a large proportion
of their lifetime. The route of treatment was appropriate. Slope factors
calculated from three data sets from two independent assays were within
a factor of 2. A slope factor for dieldrin, a major metabolite of aldrin,
was determined to be 1.6E+1, essentially identical to that of aldrin.

__II.D.1.
EPA Documentation

The values in the 1986 Carcinogenicity Assessment for
Aldrin/Dieldrin have been reviewed by the Carcinogen Assessment Group.

__II.D.2.
EPA Review (Carcinogenicity Assessment)

Agency Work Group Review — 03/22/1987

Verification Date — 03/22/1987

Screening-Level Literature Review Findings — A screening-level review conducted by an EPA contractor of the more recent toxicology literature pertinent to the cancer assessment for Aldrin conducted in September 2002 identified one or more significant new studies. IRIS users may request the references for those studies from the IRIS Hotline at hotline.iris@epa.gov or (202)566-1676.

__II.D.3.
EPA Contacts (Carcinogenicity Assessment)

Please contact the IRIS Hotline for all questions
concerning this assessment or IRIS, in general, at (202)566-1676 (phone),
(202)566-1749 (FAX) or hotline.iris@epa.gov
(internet address).

Drinking Water Health Advisories, EPA
Regulatory Actions, and Supplementary Data were removed from IRIS
on or before April 1997. IRIS users were directed to the appropriate
EPA Program Offices for this information.